Chronic Arsenic Exposure Induces Hepatocyte Proliferation in Rats via the Gut‐Liver Axis: Interventions With Fecal Microbiota Transplantation and/or Arsenic Withdrawal

ABSTRACT

Arsenic (As) contamination in groundwater has been reported in many countries and is a major risk factor for liver injury. While the impact of arsenic exposure on gut microbiota and its role in liver diseases through the gut‐liver axis has been documented, the underlying mechanism remains unclear. In this study, we established a chronic arsenic exposure rat model by administering sodium arsenite (NaAsO ₂ ) at concentrations of 30 and 100 mg/L through drinking water until 62 weeks of age. Subsequently, high As‐exposed rats were subjected to fecal microbiota transplantation (FMT), arsenic cessation, or combined FMT and arsenic cessation interventions for 2 months. Liver pathological changes, hepatocyte proliferation, intestinal microbiota composition, fecal butyrate levels, and the expression of butyrate‐related molecular markers were evaluated using hematoxylin–eosin staining, immunohistochemistry, 16S rRNA gene sequencing, gas chromatography, and quantitative real‐time PCR. Chronic arsenic exposure increased hepatocyte proliferation, as evidenced by elevated PCNA and Ki‐67 expression in liver tissues. Microbiota analysis revealed that arsenic exposure significantly altered gut microbial community structure and reduced the abundance of butyrate‐producing bacteria, particularly Lachnospiraceae and Blautia . Consistently, fecal butyrate levels showed a decreasing trend after arsenic exposure. Furthermore, arsenic exposure significantly suppressed hepatic miR‐22 expression, accompanied by increased expression of Sirt1 and Ctnnb1 and decreased expression of Gsk3b , suggesting activation of a proliferation‐related signaling pathway. Intervention with FMT and/or arsenic cessation partially restored gut microbiota composition, alleviated miR‐22 suppression, and improved arsenic‐induced molecular alterations. Collectively, these findings demonstrate that chronic arsenic exposure promotes hepatocyte proliferation through disruption of gut microbiota and reduction of microbiota‐derived butyrate, which may regulate the miR‐22/Sirt1 signaling pathway. Restoration of intestinal microbiota by FMT or cessation of arsenic exposure may provide potential strategies for mitigating arsenic‐induced hepatic abnormalities.